Redefining the role of Ca2+-permeable channels in photoreceptor degeneration using diltiazem

Das, Soumyaparna; Popp, Valerie; Power, Michael; Groeneveld, Kathrin; Yan, Jie; Melle, Christian; Rogerson, Luke; Achury, Marlly Natalia; Schwede, Frank; Straßer, Torsten; Euler, Thomas; Paquet-Durand, François; Nache, Vasilica

doi:10.1038/s41419-021-04482-1

Cited by 16 publications

(12 citation statements)

References 72 publications

(104 reference statements)

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“…A significant regulation was also observed for a group of genes that code for voltage-gated Ca 2+ -channel (VGCC) subunits, including Cacna1d , Cacnb2 , Cacna2d1 , Cacna2d2 , and Cacna2d4 . This could imply that photoreceptor Ca 2+ -levels may be influenced not only by CNG-channel activity but also by VGCCs as also suggested by recent pharmacological studies [ 30 , 31 ]. Note that of the six genes significantly regulated in cone photoreceptors, five also appear as regulated in rods ( Figure 7 ).…”

Section: Resultsmentioning

confidence: 73%

Single-Cell Transcriptomic Profiling in Inherited Retinal Degeneration Reveals Distinct Metabolic Pathways in Rod and Cone Photoreceptors

Chen

Dong²,

Yan

et al. 2022

IJMS

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The cellular mechanisms underlying hereditary photoreceptor degeneration are still poorly understood. The aim of this study was to systematically map the transcriptional changes that occur in the degenerating mouse retina at the single cell level. To this end, we employed single-cell RNA-sequencing (scRNA-seq) and retinal degeneration-1 (rd1) mice to profile the impact of the disease mutation on the diverse retinal cell types during early post-natal development. The transcriptome data allowed to annotate 43,979 individual cells grouped into 20 distinct clusters. We further characterized cluster-specific metabolic and biological changes in individual cell types. Our results highlight Ca2+-signaling as relevant to hereditary photoreceptor degeneration. Although metabolic reprogramming in retina, known as the ‘Warburg effect’, has been documented, further metabolic changes were noticed in rd1 mice. Such metabolic changes in rd1 mutation was likely regulated through mitogen-activated protein kinase (MAPK) pathway. By combining single-cell transcriptomes and immunofluorescence staining, our study revealed cell type-specific changes in gene expression, as well as interplay between Ca2+-induced cell death and metabolic pathways.

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Section: Resultsmentioning

confidence: 73%

Single-Cell Transcriptomic Profiling in Inherited Retinal Degeneration Reveals Distinct Metabolic Pathways in Rod and Cone Photoreceptors

Chen

Dong²,

Yan

et al. 2022

IJMS

View full text Add to dashboard Cite

show abstract

“…A significant regulation was also observed for a group of genes that code for voltage-gated Ca 2+ -channel (VGCC) subunits, including Cacna1d, Cacnb2, Cacna2d1, Cacna2d2, and Cacna2d4. This could imply that photoreceptor Ca 2+ -levels may be influenced not only by CNG-channel activity but also by VGCCs as suggested also by recent pharmacological studies [30,31]. Note that of the six genes significantly regulated in cone photoreceptors five also appear as regulated in rods (Figure 7).…”

Section: The Mapk Signaling Pathway Coordinates Energy Metabolism And...mentioning

confidence: 60%

Single-cell transcriptomic profiling in inherited retinal degeneration reveals distinct metabolic pathways in rod and cone photoreceptors

Chen

Dong²,

Yan

et al. 2022

Preprint

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The cellular mechanisms underlying hereditary photoreceptor degeneration are still poorly understood. The aim of this study was to systematically map the transcriptional changes that occur in the degenerating mouse retina at the single cell level. To this end, we employed single cell RNA-sequencing (scRNA-seq) and retinal degeneration-1 (rd1) mice to profile the impact of the disease mutation on the diverse retinal cell types during early post-natal development. The transcriptome data allowed to annotate 43,979 individual cells grouped into 20 distinct retinal cell types. We further characterized cluster-specific metabolic and biological changes in individual cell types. Our results highlight Ca2+-signalling as relevant to hereditary photoreceptor degeneration. Though metabolic reprogramming in retina, known as 'Warburg effect', has been documented, further metabolic changes were noticed in rd1 mice. Such metabolic changes in rd1 mutation was likely regulated through mitogen-activated protein kinase (MAPK) pathway. By combining single-cell transcriptomes and immunofluorescence staining, our study revealed cell type-specific changes in gene expression, as well as interplay between Ca2+ induced cell death and metabolic pathways.

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“…Further co-staining experiments, including with other calpain isoforms and other signaling molecules involved in cGMP-dependent cell death, could help to unravel the time course of photoreceptor degeneration more precisely. Due to a lack of available antibodies and the lethality of certain calpain knockout models [ 49 , 50 ], this may require the development of an appropriate methodology.…”

Section: Discussionmentioning

confidence: 99%

Visualizing Cell Death in Live Retina: Using Calpain Activity Detection as a Biomarker for Retinal Degeneration

Belhadj

Hermann

Zhu

et al. 2022

IJMS

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Calpains are a family of calcium-activated proteases involved in numerous disorders. Notably, previous studies have shown that calpain activity was substantially increased in various models for inherited retinal degeneration (RD). In the present study, we tested the capacity of the calpain-specific substrate t-BOC-Leu-Met-CMAC to detect calpain activity in living retina, in organotypic retinal explant cultures derived from wild-type mice, as well as from rd1 and RhoP23H/+ RD-mutant mice. Test conditions were refined until the calpain substrate readily detected large numbers of cells in the photoreceptor layer of RD retina but not in wild-type retina. At the same time, the calpain substrate was not obviously toxic to photoreceptor cells. Comparison of calpain activity with immunostaining for activated calpain-2 furthermore suggested that individual calpain isoforms may be active in distinct temporal stages of photoreceptor cell death. Notably, calpain-2 activity may be a relatively short-lived event, occurring only towards the end of the cell-death process. Finally, our results support the development of calpain activity detection as a novel in vivo biomarker for RD suitable for combination with non-invasive imaging techniques.

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Redefining the role of Ca2+-permeable channels in photoreceptor degeneration using diltiazem

Cited by 16 publications

References 72 publications

Single-Cell Transcriptomic Profiling in Inherited Retinal Degeneration Reveals Distinct Metabolic Pathways in Rod and Cone Photoreceptors

Single-Cell Transcriptomic Profiling in Inherited Retinal Degeneration Reveals Distinct Metabolic Pathways in Rod and Cone Photoreceptors

Single-cell transcriptomic profiling in inherited retinal degeneration reveals distinct metabolic pathways in rod and cone photoreceptors

Visualizing Cell Death in Live Retina: Using Calpain Activity Detection as a Biomarker for Retinal Degeneration

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